ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Arina Riabinska; Daria Lehrmann; Ron Daniel Jachimowicz; Gero Knittel; Christian Fritz; Anna Schmitt; Aenne Geyer; Carola Heneweer; Maike Wittersheim; Lukas P. Frenzel; Alessandro Torgovnick; Janica Lea Wiederstein; Claudia Maria Wunderlich; Monika Ortmann; Arlette Paillard; Wilhelm Wößmann; Arndt Borkhardt; Stefan Burdach; Martin Leo Hansmann; Andreas Rosenwald; Sven Perner; Gita Mall; Wolfram Klapper; Andrea Merseburg; Marcus Krüger; Holger Grüll; Thorsten Persigehl; Frank Thomas Wunderlich; Martin Peifer; Olaf Utermöhlen; Reinhard Büttner; Filippo Beleggia; Hans Christian Reinhardt

doi:10.1038/s41375-019-0618-2

ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Arina Riabinska^*, Daria Lehrmann, Ron Daniel Jachimowicz, Gero Knittel, Christian Fritz, Anna Schmitt, Aenne Geyer, Carola Heneweer, Maike Wittersheim, Lukas P. Frenzel, Alessandro Torgovnick, Janica Lea Wiederstein, Claudia Maria Wunderlich, Monika Ortmann, Arlette Paillard, Wilhelm Wößmann, Arndt Borkhardt, Stefan Burdach, Martin Leo Hansmann, Andreas RosenwaldSven Perner, Gita Mall, Wolfram Klapper, Andrea Merseburg, Marcus Krüger, Holger Grüll, Thorsten Persigehl, Frank Thomas Wunderlich, Martin Peifer, Olaf Utermöhlen, Reinhard Büttner, Filippo Beleggia, Hans Christian Reinhardt

^*Corresponding author for this work

Institute of Pathology

13 Citations (Scopus)

Abstract

The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.

Original language	English
Journal	Leukemia
Volume	34
Issue number	3
Pages (from-to)	771-786
Number of pages	16
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-019-0618-2
Publication status	Published - 01.03.2020

Funding

Acknowledgements This work was supported through the Cologne Center for Genomics of the University of Cologne. We thank Prof. Peter Nürnberg, Dr. Janine Altmüller and Dr. Graziella Bosco (University of Cologne, Germany) for help with RNA-and whole exome sequencing. Financial support This work was supported by the Volkswagen-stiftung (Lichtenberg Program, HCR), the Deutsche For-schungsgemeinschaft (KFO-286, LPF and HCR, JA 2439/1-1 to RDJ), the Bundesministerium für Bildung und Forschung (SMOOSE, HCR), the German federal state NRW (EFRE initiative, LS-1-1-030a, HCR), the Else Kröner-Fresenius Stiftung (EKFS-2014-A06, HCR, 2016-Kolleg-19 to RDJ), the Deutsche Krebshilfe (111724, HCR) and the Jose Carreras Stiftung (DJCLS-R12/26, LPF and HCR). Conflict of interest HCR received consulting fees from Abbvie, AstraZeneca, Vertex, and Merck and research funding from Gilead. The remaining authors declare that they have no conflict of interest.

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Riabinska, A., Lehrmann, D., Jachimowicz, R. D., Knittel, G., Fritz, C., Schmitt, A., Geyer, A., Heneweer, C., Wittersheim, M., Frenzel, L. P., Torgovnick, A., Wiederstein, J. L., Wunderlich, C. M., Ortmann, M., Paillard, A., Wößmann, W., Borkhardt, A., Burdach, S., Hansmann, M. L., ... Reinhardt, H. C. (2020). ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia, 34(3), 771-786. https://doi.org/10.1038/s41375-019-0618-2

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title = "ATM activity in T cells is critical for immune surveillance of lymphoma in vivo",

abstract = "The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.",

author = "Arina Riabinska and Daria Lehrmann and Jachimowicz, \{Ron Daniel\} and Gero Knittel and Christian Fritz and Anna Schmitt and Aenne Geyer and Carola Heneweer and Maike Wittersheim and Frenzel, \{Lukas P.\} and Alessandro Torgovnick and Wiederstein, \{Janica Lea\} and Wunderlich, \{Claudia Maria\} and Monika Ortmann and Arlette Paillard and Wilhelm W{\"o}{\ss}mann and Arndt Borkhardt and Stefan Burdach and Hansmann, \{Martin Leo\} and Andreas Rosenwald and Sven Perner and Gita Mall and Wolfram Klapper and Andrea Merseburg and Marcus Kr{\"u}ger and Holger Gr{\"u}ll and Thorsten Persigehl and Wunderlich, \{Frank Thomas\} and Martin Peifer and Olaf Uterm{\"o}hlen and Reinhard B{\"u}ttner and Filippo Beleggia and Reinhardt, \{Hans Christian\}",

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doi = "10.1038/s41375-019-0618-2",

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Riabinska, A, Lehrmann, D, Jachimowicz, RD, Knittel, G, Fritz, C, Schmitt, A, Geyer, A, Heneweer, C, Wittersheim, M, Frenzel, LP, Torgovnick, A, Wiederstein, JL, Wunderlich, CM, Ortmann, M, Paillard, A, Wößmann, W, Borkhardt, A, Burdach, S, Hansmann, ML, Rosenwald, A, Perner, S, Mall, G, Klapper, W, Merseburg, A, Krüger, M, Grüll, H, Persigehl, T, Wunderlich, FT, Peifer, M, Utermöhlen, O, Büttner, R, Beleggia, F & Reinhardt, HC 2020, 'ATM activity in T cells is critical for immune surveillance of lymphoma in vivo', Leukemia, vol. 34, no. 3, pp. 771-786. https://doi.org/10.1038/s41375-019-0618-2

TY - JOUR

T1 - ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

AU - Riabinska, Arina

AU - Lehrmann, Daria

AU - Jachimowicz, Ron Daniel

AU - Knittel, Gero

AU - Fritz, Christian

AU - Schmitt, Anna

AU - Geyer, Aenne

AU - Heneweer, Carola

AU - Wittersheim, Maike

AU - Frenzel, Lukas P.

AU - Torgovnick, Alessandro

AU - Wiederstein, Janica Lea

AU - Wunderlich, Claudia Maria

AU - Ortmann, Monika

AU - Paillard, Arlette

AU - Wößmann, Wilhelm

AU - Borkhardt, Arndt

AU - Burdach, Stefan

AU - Hansmann, Martin Leo

AU - Rosenwald, Andreas

AU - Perner, Sven

AU - Mall, Gita

AU - Klapper, Wolfram

AU - Merseburg, Andrea

AU - Krüger, Marcus

AU - Grüll, Holger

AU - Persigehl, Thorsten

AU - Wunderlich, Frank Thomas

AU - Peifer, Martin

AU - Utermöhlen, Olaf

AU - Büttner, Reinhard

AU - Beleggia, Filippo

AU - Reinhardt, Hans Christian

PY - 2020/3/1

Y1 - 2020/3/1

N2 - The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.

AB - The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.

UR - https://www.scopus.com/pages/publications/85074749885

U2 - 10.1038/s41375-019-0618-2

DO - 10.1038/s41375-019-0618-2

M3 - Journal articles

C2 - 31690822

AN - SCOPUS:85074749885

SN - 0887-6924

VL - 34

SP - 771

EP - 786

JO - Leukemia

JF - Leukemia

IS - 3

ER -

ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Abstract

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